Project Summary/Abstract Panic attacks are a common symptom in patients suffering from numerous anxiety disorders. These overwhelming attacks are particularly common populations with severe trauma, such as rape victims or veterans. Circuits mediating escape from imminent threats such as asphyxiation are strongly implicated in the generation of panic attacks. Naturalistic escape from threats occur in complex environments in which animals must quickly flee through the most efficient route. A single incorrect choice of context-specific escape plan may result in death. Prior studies have identified regions that produce escape movements during neural stimulation, such as jumping. However, these movements often do not result in choice of optimal escape routes. To date, circuits inducing context-specific choice of escape routes have not been identified. Now, we show that optogenetic stimulation of nitric oxide synthase1 (nos1)+ cells in the dorsal premammillary nucleus (PMd) creates context-specific escape, similarly to naturalistic escape. In an empty box, PMD stimulation causes jumping, but after adding a climbing rope escape, stimulation causes escape by climbing the rope. In contrast, stimulation of the dorsolateral periaqueductal gray (dlPAG), which is the region most deeply studied in panic-related escape, causes jumping and running in all situations, even when these actions do not allow escape. Intriguingly, the PMd is the densest input to the panic-inducing dlPAG, but it has never been activated directly. Activation of the nos1+PMd-dlPAG projection also led to the same panic-related symptoms as stimulation of nos1 PMd cell bodies, including escape and aversion. This finding suggests the PMd is creating context-specific escape by acting on the dlPAG. To study this circuit, we developed two novel paradigms with escape-provoking threats: a corridor containing a live predator (an awake rat that is not separated by a barrier) and a chamber for exposure to 15% CO2, a stimulus known to cause panic in humans. In both paradigms threat exposure can only be maximized with context-specific escape plans requiring coordinated action. These paradigms produce a full range of defensive behaviors (risk- assessment, freezing, jumping/running and planned escape using optimal routes) depending on threat intensity (distance to rat or CO2 concentration), allowing us to precisely identify which behaviors are controlled by the PMd-dlPAG circuit. Our aims are to: 1) Optogenetically dissect how the PMd-dlPAG circuit produces these symptoms, 2) Characterize how panicogenic threats affect PMd activity and synchrony in the PMd-dPAG circuit and 3) Examine how PMd input influences threat-encoding in the dlPAG and how it synaptically affects dlPAG cells. Since PMd-dlPAG activation selectively induced escape, but not other defensive behaviors, we hypothesize that the nos1+PMd-dlPAG circuit specifically affects planned context-specific escape. We also predict that neural activity in this circuit is most strongly correlated with escape. These aims will reveal novel circuit mechanisms underlying panic-related escape from threat.